A growing body of evidence indicates that myostatin (mstn, Growth and Differentiation Factor-8, or GDF-8) negatively regulates skeletal muscle growth. For example, a myostatin null mutation in a child has been associated with dramatic muscle hypertrophy without any obvious abnormalities (Schuelke et al. (2004) Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child. New Engl. J. Med. 350:2682-8). A negative correlation between muscle myostatin protein levels and skeletal muscle mass has also been demonstrated (Schulte, J. N. and Yarasheski, K. E. (2001). Effects of resistance training on the rate of muscle protein synthesis in frail elderly people. Int. J. Sport Nutr. Exerc. Metab. 11 Suppl:S111-820; Walker K S et al. (2004) Resistance training alters plasma myostatin but not IGF-1 in healthy men. Med Sci Sports Exerc. 36(5):787-93.). For example, there is an increased expression of muscle myostatin levels with age and increased myostatin expression has also been shown to contribute to muscle wasting in HIV-infected patients (Gonzalez-cadavid et al. (1998) Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. PNAS 95:14938-4321). In addition, elevated myostatin levels are found in elderly populations. (Yarasheski K E et al., (2002) Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting. J. Nutr. Health Aging. 6(5):343-8). Myostatin also influences bone mass as myostatin-deficient mice have increased bone mineral density (Hamrick et al., (2003) Bone Architecture and Disc Degeneration in the Lumbar Spine of Mice Lacking GDF-8 (Myostatin). J. Orthopaedic Res. 21: 1025-1032 (and references therein).
Antibodies to circulating myostatin have been shown to cause increased muscle mass and improved glucose homeostasis in murine models of type 2 diabetes mellitus. Inhibition of myostatin by ip injection of a neutralizing antibody increases skeletal muscle mass, lowers fasting blood glucose and improves glucose sensitivity in obese diabetic mice (Li X. et al. (2002) Inhibition of myostatin increases muscle mass and improves glucose sensitivity in obese, diabetic mice. Poster #224, in Keystone Symposia: Diabetes Mellitus: Molecular Mechanisms, Genetics and New Therapies). In addition, Ay/a mice are known to develop insulin resistance and are used as a model for type 2 diabetes. When Ay/a mice are made devoid of myostatin by deletion of the myostatin locus, they have normal fed glucose and insulin levels, and dramatically lower glucose levels following an exogenous glucose load relative to normal Ay/amice (McPherron et al. (2002) J. Clin. Invest. 109:595-601).
Considering the detrimental muscle, bone and metabolic defects associated with myostatin, there is an urgent need for antibodies as therapeutics that are specific for myostatin and which prevent or treat conditions by reducing myostatin activity, as well as antibodies as diagnostics to identify individuals that are in need of treatment to reduce myostatin activity.